Protein acetylation-dependent fatty acid metabolic dysfunction in HFpEF

项目摘要 心力衰竭伴保留射血分数占所有心力衰竭患者的≈的50%， 与显著的发病率、死亡率和医疗保健支出相关。然而，目前还没有有效的治疗方法 HFpEF已被鉴定。通常与其他代谢性疾病并存，HFpEF被认为是 全身代谢紊乱的心血管表现。然而，人们对其潜在的原因知之甚少。 机械装置。我们的实验室最近开发并验证了一种新的小鼠模型，它可以准确地重述 人HFpEF的大部分临床特征。使用这个新的小鼠模型，我发现了重要的线粒体 与线粒体蛋白高乙酰化相关的HFpEF心肌功能障碍，这是一个关键的后 已知的调节酶活性的翻译修饰。这导致了我们的中心假设，即蛋白质 高乙酰化是HFpEF线粒体功能障碍和代谢重塑的可逆驱动因素，并可能 作为有意义的治疗靶点。在这项提案中，我们的目标是(1)确定主要的 线粒体脱乙酰酶，在调节线粒体功能和HFpEF发病机制中的作用；(2)鉴定特异性 高乙酰化影响HFpEF线粒体功能的靶点；(3)确定治疗 调节蛋白乙酰化对HFpEF线粒体功能和心脏表型的影响。总而言之， 这些研究将对我们理解HFpEF的病理生理学和潜在的 推出有效治疗HFpEF的新疗法。此外，这里提出的工作，加上全面的 培训计划，将为我提供开始职业生涯所需的额外知识和技能 成功且完全独立的内科医生兼科学家。

Project Summary Heart failure with preserved ejection fraction (HFpEF) accounts for ≈50% of all patients with heart failure, and is associated with significant morbidity, mortality, and health care expenditures. Yet, no effective treatment for HFpEF has been identified. Commonly coexisting with other metabolic diseases, HFpEF is considered the cardiovascular manifestation of a systemic metabolic disturbance. However, little is known about its underlying mechanisms. Our laboratory recently developed and validated a novel mouse model that faithfully recapitulates most clinical features of human HFpEF. Using this novel mouse model, I discovered significant mitochondrial dysfunction in HFpEF myocardium, which is associated with mitochondrial protein hyperacetylation, a key post- translational modification known to regulate enzymatic activities. This led to our central hypothesis that protein hyperacetylation is a reversible driver of mitochondrial dysfunction and metabolic remodeling in HFpEF and could serve as a meaningful therapeutic target. In this proposal, we aim to (1) Determine the role of Sirtuin 3, the major mitochondrial deacetylase, in regulating mitochondrial function and HFpEF pathogenesis; (2) Identify specific targets through which hyperacetylation impacts mitochondrial function in HFpEF; (3) Determine the therapeutic effect of modulating protein acetylation on HFpEF mitochondrial function and cardiac phenotype. Collectively, these studies will have a meaningful impact on our understanding of HFpEF pathophysiology and potentially unveil novel therapy to effectively treat HFpEF. Furthermore, work proposed here, coupled with a comprehensive training plan, will provide me with the additional knowledge and skills required to launch my career as a successful and fully independent physician-scientist.